Department of Gynecologic Oncology, Hyogo Cancer Center, Akashi, Hyogo, Japan.
Transl Res. 2013 Sep;162(3):181-90. doi: 10.1016/j.trsl.2013.06.005. Epub 2013 Jul 12.
Ovarian cancer is the most lethal gynecological malignancy in the western world. Although patients with early-stage ovarian cancer generally have a good prognosis, approximately 20%-30% of patients will die of the disease, and 5-year recurrence rates are 25%-45%, highlighting the need for improved detection and treatment. We investigated the role of VAV1, a protein with guanine nucleotide exchange factor activity, which is associated with survival in patients with early-stage ovarian cancer (International of Obstetrics and Gynecology [FIGO] stages I and II). We analyzed 88 samples from patients with primary epithelial ovarian cancer, which were divided into FIGO stages I and II (n = 46), and III and IV (n = 42). Prognostic analysis revealed that upregulated VAV1 expression correlated significantly with poor prognosis in patients with early-stage epithelial ovarian cancer (P ≤ 0.05), but not with other clinicopathologic features. Stable overexpression of VAV1 in human high-grade serous ovarian cancer SKOV3 cells induced morphologic changes indicative of loss of intercellular adhesions and organized actin stress fibers. Western blotting and real-time reverse transcriptase-polymerase chain reaction demonstrated that these cells had downregulated E-cadherin protein and messenger RNA levels, respectively. This downregulation is associated with epithelial-mesenchymal transition (EMT) and invasive cancer. Furthermore, VAV1 overexpression in both SKOV3 and human ovarian surface epithelial cells demonstrated that its upregulation of an E-cadherin transcriptional repressor, Snail and Slug, was not confined to ovarian cancer cells. Conversely, knockdown of VAV1 by RNA interference reduced Snail and Slug. Our findings suggest that VAV1 may play a role in the EMT of ovarian cancer, and may serve as a potential therapeutic target.
卵巢癌是西方世界最致命的妇科恶性肿瘤。尽管早期卵巢癌患者的预后通常较好，但约 20%-30%的患者会死于该疾病，且 5 年复发率为 25%-45%，这突出表明需要改进检测和治疗方法。我们研究了 VAV1 的作用，VAV1 是一种具有鸟嘌呤核苷酸交换因子活性的蛋白，与早期卵巢癌（国际妇产科联盟[FIGO]I 期和 II 期）患者的生存相关。我们分析了 88 例原发性上皮性卵巢癌患者的样本，这些患者分为 FIGO I 期和 II 期（n=46）和 III 期和 IV 期（n=42）。预后分析显示，早期上皮性卵巢癌患者中上调的 VAV1 表达与不良预后显著相关（P≤0.05），但与其他临床病理特征无关。在人高级别浆液性卵巢癌 SKOV3 细胞中稳定过表达 VAV1 诱导了细胞间黏附丧失和有组织的肌动蛋白应力纤维的形态变化。Western blot 和实时逆转录-聚合酶链反应显示，这些细胞的 E-钙黏蛋白蛋白和信使 RNA 水平分别下调。这种下调与上皮间质转化（EMT）和侵袭性癌症有关。此外，VAV1 在 SKOV3 和人卵巢表面上皮细胞中的过表达表明，其对 E-钙黏蛋白转录抑制剂 Snail 和 Slug 的上调不仅限于卵巢癌细胞。相反，通过 RNA 干扰敲低 VAV1 可降低 Snail 和 Slug。我们的研究结果表明，VAV1 可能在卵巢癌的 EMT 中发挥作用，并可能成为一个潜在的治疗靶点。
